DESCRIPTION: Neonatal rats fed a high-carbohydrate (HC) milk formula using an artificial rearing system during the suckling period experience alterations in the insulin content and secretory activity of the pancreatic beta cells. Neonatal hyperinsulinemia (HI) is a consequence which persists in adult life, in addition to impaired glucose tolerance and obesity only in adult rats. In addition, progeny of HC rats display HI, and altered glucose tolerance and obesity in later life. The goals of this project are to investigate the mechanisms responsible for early adaptive modifications in pancreatic islet cells in response to a HC diet and also metabolic adaptations in fetal pancreas of HI rats. Three specific aims are to: (1) To investigate the mechanism(s) responsible for altered insulin secretory response in pancreatic islets from first generation HC rats. Plasma free fatty acid and triglyceride levels will be determined during development of HI. The hypothesis is that a high carbohydrate diet fed early in life affects fuel metabolism in the pancreatic beta cell which modifies insulin secretion and persists in adult life. (2) Investigate the influence of maternal HI on the development of an altered insulin secretory response in the postnatal life of offspring. (3) Determine the activity of specific second messenger systems in islets derived from neonatal, junvenile and adult rats reared on mother's milk (MF rats) or on a diet enriched in fat (HF rats) or carbohydrate (HC rats). The hypothesis is that continuous glucose stimulation at an early age alters the glucose transporter (GLUT-2), glucose metabolizing enzymes, adenylate cyclase and the enzymes/proteins which contribute to the functioning of the phosphoinositide pathway and the ability of the beta cell to regulate insulin secretion in a normal fashion. This unique rat model has the potential for providing new and significant insight into the "fuel hypothesis" for altered insulin secretory response in response to diet and maternal influences on fetal pancreatic adaptations.